Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B

Familial hypercholesterolemia (FH) due to a founder variant in Apolipoprotein B (ApoB^R3500Q) is reported in 12% of the Pennsylvania Amish community. By studying a cohort of ApoB^R3500Q heterozygotes and homozygotes, we aimed to characterize the biochemical and cardiac imaging features in children and young adults with a common genetic background and similar lifestyle.

We employed advanced lipid profile testing, carotid intima media thickness (CIMT), pulse wave velocity (PWV), and peripheral artery tonometry (PAT) to assess atherosclerosis in a cohort of Amish ApoB^R3500Q heterozygotes (n = 13), homozygotes (n = 3), and their unaffected, age-matched siblings (n = 9). ApoB^R3500Q homozygotes were not included in statistical comparisons.

LDL cholesterol (LDL-C) was significantly elevated among ApoB^R3500Q heterozygotes compared to sibling controls, though several ApoB^R3500Q heterozygotes had LDL-C levels in the normal range. LDL particles (LDL-P), small, dense LDL particles, and ApoB were also significantly elevated among subjects with ApoB^R3500Q. Despite these differences in serum lipids and particles, CIMT and PWV were not significantly different between ApoB^R3500Q heterozygotes and controls in age-adjusted analysis.

We provide a detailed description of the serum lipids, atherosclerotic plaque burden, vascular stiffness, and endothelial function among children and young adults with FH due to heterozygous ApoB^R3500Q. Fasting LDL-C was lower than what is seen with other forms of FH, and even normal in several ApoB^R3500Q heterozygotes, emphasizing the importance of cascade genetic testing among related individuals for diagnosis. We found increased number of LDL particles among ApoB^R3500Q heterozygotes but an absence of detectable atherosclerosis.